Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Werner syndrome (WS) is an autosomal recessive condition characterized by an early onset of age-related symptoms that include ocular cataracts, premature graying and loss of hair, arteriosclerosis and atherosclerosis, diabetes mellitus, osteoporosis, and a high incidence of some types of cancers. A major motivation for the study of WS is the expectation that elucidation of its underlying mechanisms will illuminate the basis for "normal" aging. In 1996, the gene responsible for the syndrome was positionally cloned. This advance launched an explosion of experiments aimed at unraveling the molecular mechanisms that lead to the WS phenotype. Soon thereafter, its protein product, WRN, was expressed, purified, and identified as a DNA helicase-exonuclease, a bifunctional enzyme that both unwinds DNA helices and cleaves nucleotides one at a time from the end of the DNA. WRN was shown to interact physically and functionally with several DNA-processing proteins, and WRN transgenic and null mutant mouse strains were generated and described. The substantial number of excellent reviews on WRN and WS that were published in the past 2 years (1-7) reflects the rapid pace of advances made in the field. Unlike those comprehensive articles, this review focuses on the biochemistry of the WRN protein and some aspects of its cell biology. Also considered are the putative functions of WRN in normal cells and the consequences of the loss of these functions in WS.
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PMID:The Werner syndrome helicase-nuclease--one protein, many mysteries. 1460 80

Mutations in human WRN (also known as RECQ3) gene give rise to a rare autosomal recessive genetic disorder, Werner syndrome (WS). WS is a premature aging disease characterized by predisposition to cancer and early onset of symptoms related to normal aging including osteoporosis, ocular cataracts, graying and loss of hair, diabetes mellitus, arteriosclerosis, and atherosclerosis. This review focuses on the functional role of Werner protein (WRN) in guarding the genetic stability of cells, particularly by playing an integral role in the base excision repair, and at the telomere ends. Furthermore, in-depth biochemical investigations have significantly advanced our understanding of WRN protein regarding its binding partners and the site of protein-protein interaction. The mapping analysis of protein interaction sites in WRN for most of its binding partners have revealed a common site of protein-protein interaction in the RecQ conserved (RQC) region of WRN.
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PMID:Pathways and functions of the Werner syndrome protein. 1561 Jul 65

Werner syndrome (WS) is characterized by the early onset of senescent phenotypes including premature atherosclerotic cardiovascular diseases, although the underlying molecular mechanism for atherosclerosis has not been fully understood yet. Cholesterol efflux from the cells is the initial step of reverse cholesterol transport, a major protective system against atherosclerosis. The aim of the present study was to determine whether this crucial step may be altered in WS. We examined intracellular lipid transport and cholesterol efflux and the expression levels of its related molecules in skin fibroblasts obtained from patients with WS. Cholesterol efflux was markedly reduced in the WS fibroblasts in association with increased cellular cholesterol. Fluorescent recovery after photobleaching (FRAP) technique revealed that intracellular lipid transport around Golgi apparatus was markedly reduced when using a C6-NBD-Ceramide as a tracer. Cdc42 protein and its GTP-bound form were markedly reduced in the WS fibroblasts. The complementation of wild-type Cdc42 corrected cholesterol efflux, intracellular lipid transport, and cellular cholesterol levels in the WS fibroblasts. These data indicated that the reduced expression of Cdc42 may be responsible for the abnormal lipid transport, which in turn might be related to the cardiovascular manifestations in WS.
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PMID:Defective cholesterol efflux in Werner syndrome fibroblasts and its phenotypic correction by Cdc42, a RhoGTPase. 1582 Jun 9

Werner syndrome (WS) is an autosomal recessive premature aging disease manifested by the mimicry of age-related phenotypes such as atherosclerosis, arteriosclerosis, cataracts, osteoporosis, soft tissue calcification, premature thinning, graying, and loss of hair, as well as a high incidence of some types of cancers. The gene product defective in WS, WRN, is a member of the RecQ family of DNA helicases that are widely distributed in nature and believed to play central roles in genomic stability of organisms ranging from prokaryotes to mammals. Interestingly, WRN is a bifunctional protein that is exceptional among RecQ helicases in that it also harbors an exonuclease activity. Furthermore, it preferentially operates on aberrant DNA structures believed to exist in vivo as intermediates in specific DNA transactions such as replication (forked DNA), recombination (Holliday junction, triplex and tetraplex DNA), and repair (partial duplex with single stranded bubble). In addition, WRN has been shown to physically and functionally interact with a variety of DNA-processing proteins, including those that are involved in resolving alternative DNA structures, repair DNA damage, and provide checkpoints for genomic stability. Despite significant research activity and considerable progress in understanding the biochemical and molecular genetic function of WRN, the in vivo molecular pathway(s) of WRN remain elusive. The following review focuses on the recent advances in the biochemistry of WRN and considers the putative in vivo functions of WRN in light of its many protein partners.
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PMID:Current advances in unraveling the function of the Werner syndrome protein. 1594 10

Werner syndrome is a genetic disease characterized by early ageing, excess cancer risk, high incidence of type II diabetes mellitus, early atherosclerosis, ocular cataracts, and osteoporosis. The protein encoded by the defective gene, WRN (WRNp) associates with three activities, that is, a RecQ DNA helicase, 3'-5'-exonuclease and ATPase activities. By highlighting the DNA helicase activity, a widespread consensus in WS-associated defect(s) has been established, pointing toward a deficiency in maintaining DNA integrity. However, a possible involvement of redox pathways in WS may be suggested by several lines of evidence that include: (i) the multiple functions and interactions of WRNp with oxidative stress-related activities and factors; (ii) the pleiotropic WS clinical phenotype encompassing a number of oxidative stress-related pathologies; (iii) redox-related toxicity mechanisms of several xenobiotics exerting excess toxicity in WS cells; (iv) recent in vivo and in vitro findings of redox abnormalities in WS patients and in WS cells. The working hypothesis is raised that a deficiency in WRNp, and the pleiotropic clinical phenotype in WS patients may provide the basis to envision an underlying in vivo prooxidant state, which causes oxidative damage to biomolecules, with multiple oxidative stress-related alterations, resulting in multi-faceted clinical consequences.
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PMID:Multiple involvement of oxidative stress in Werner syndrome phenotype. 1633 57

Werner syndrome (WS) is a pleiotropic disease of premature aging involving short stature, tight, atrophied, and/or ulcerated skin; a characteristic 'birdlike' facies and high, squeaky or hoarse voice; premature greying and thinning of the hair; and early onset cataracts. Additional common symptoms include diabetes mellitus, hypogonadism, osteoporosis, osteosclerosis of the digits, soft tissue calcification, premature atherosclerosis, rare or multiple neoplasms, malformed teeth, and flat feet. Diagnosis can be difficult due to the variable presentation and rarity of the disorder. Transmission is usually autosomal recessive. The WS gene, WRN, is member of the RecQ DNA helicase family. Biallelic mutations of WRN are responsible for most patients. Although heterozygous missense mutations in the LMNA gene have been observed in severely affected WS patients, this only accounts for a small fraction of non-WRN patients. Eighteen WS cases were referred to us for molecular analysis. Eleven had definite and three had probable WS according to the University of Washington Registry clinical criteria. All exons of the WRN gene and their splice junctions were sequenced. Of the fourteen definite or probable cases, 11 had one or more WRN mutation. Thirteen different mutations were found, and ten of these were previously undescribed. There were few phenotypic differences between patients with WRN mutation(s) and those who met clinical criteria though lacking WRN mutations. However, patients with mutations tended to have more symptoms overall, and mutations were not observed in the two cases with cardiomyopathy.
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PMID:Werner syndrome and mutations of the WRN and LMNA genes in France. 1678 14

Werner syndrome is a premature aging disease characterized by genomic instability and increased cancer risk. Here, we report a 45-year-old diabetic man as the first Werner syndrome patient found to have an adiponectin gene mutation. Showing graying and loss of hair, skin atrophy, and juvenile cataract, he was diagnosed with Werner syndrome type 4 by molecular analysis. His serum adiponectin concentration was low. In the globular domain of the adiponectin gene, I164T in exon 3 was detected. When we examined effects of pioglitazone (15 mg/day) on serum adiponectin multimer and monomer concentrations using selective assays, the patient's relative percentage increased in adiponectin concentration was almost same as that in the 18 diabetic patients without an adiponectin mutation, but the absolute adiponectin concentration was half of those seen in diabetic patients treated with the same pioglitazone dose who had no adiponectin mutation. The response suggested that pioglitazone treatment might help to prevent future Werner syndrome-related acceleration of atherosclerosis. Present and further clinical relevant to atherosclerosis in this patient should be imformative concerning the pathogenesis and treatment of atherosclerosis in the presence of hypoadiponectinemia and insulin resistance.
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PMID:A patient with Werner syndrome and adiponectin gene mutation. 1680 59

Werner syndrome (WS) is a premature aging disorder that is widely used as a model for some aspects of the normal human aging process. Individuals with WS have several of the characteristics of normal aging, such as cataracts, hair graying, and skin aging, but manifest these at an early age. In addition, WS is associated with high levels of inflammatory diseases such as atherosclerosis and type II diabetes. Recent data have indicated that fibroblasts derived from individuals with WS have activated a major molecular pathway involved in inflammation. This observation ties in with the presence of high plasma levels of inflammatory cytokines in individuals with WS. In this paper, the authors discuss the possibility that WS is an example of "inflamm-aging," in that many of the phenotypic manifestations may result from an increased inflammatory state. Moreover, drugs that specifically block this inflammation pathway may be possible candidates for therapeutic intervention in WS.
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PMID:Werner Syndrome as an example of inflamm-aging: possible therapeutic opportunities for a progeroid syndrome? 1685 81

The Werner syndrome helicase (WRN) participates in DNA replication, double strand break repair, telomere maintenance, and p53 activation. Mutations of wrn cause Werner syndrome (WS), an autosomal recessive premature aging disorder associated with cancer predisposition, atherosclerosis, and other aging related symptoms. Here, we report that WRN is a novel cofactor for HIV-1 replication. Immortalized human WRN(-/-) WS fibroblasts, lacking a functional wrn gene, are impaired for basal and Tat-activated HIV-1 transcription. Overexpression of wild-type WRN transactivates the HIV-1 long terminal repeat (LTR) in the absence of Tat, and WRN cooperates with Tat to promote high-level LTR transactivation. Ectopic WRN induces HIV-1 p24(Gag) production and retroviral replication in HIV-1-infected H9(HIV-1IIIB) lymphocytes. A dominant-negative helicase-minus mutant, WRN(K577M), inhibits LTR transactivation and HIV-1 replication. Inhibition of endogenous WRN, through co-expression of WRN(K577M), diminishes recruitment of p300/CREB-binding protein-associated factor (PCAF) and positive transcription elongation factor b (P-TEFb) to Tat/transactivation response-RNA complexes, and immortalized WRN(-/-) WS fibroblasts exhibit comparable defects in recruitment of PCAF and P-TEFb to the HIV-1 LTR. Our results demonstrate that WRN is a novel cellular cofactor for HIV-1 replication and suggest that the WRN helicase participates in the recruitment of PCAF/P-TEFb-containing transcription complexes. WRN may be a plausible target for antiretroviral therapy.
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PMID:The Werner syndrome helicase is a cofactor for HIV-1 long terminal repeat transactivation and retroviral replication. 1731 67

Werner syndrome (WS) is a premature aging disorder used as a model of normal human aging. WS individuals have several characteristics of normal aging, such as cataracts, hair graying, and skin aging, but manifest these at an early age. Additionally, WS individuals have high levels of inflammatory diseases, such as atherosclerosis and type 2 diabetes. The in vivo aging in WS is associated with accelerated aging of fibroblasts in culture. The cause of the accelerated senescence is not understood, but may be due to the genomic instability that is a hallmark of WS. Genome instability results in activation of stress kinases, such as p38, and the p38-specific inhibitor SB203580, prevents the accelerated senescence seen in WS fibroblasts. However, oxidative damage plays a role, as low oxygen conditions and antioxidant treatment revert some of the accelerated senescence phenotype. The effects of oxidative stress appear to be suppressible by SB203580; however, it does not appear to be transduced by p38. As SB203580 is known to inhibit other kinases in addition to p38, this suggests that more than one kinase pathway is involved. The recent development of p38 inhibitors with different binding properties, specificities, and oral bioavailability, and of new potent and selective inhibitors of JNK and MK2, will make it possible to dissect the roles of various kinase pathways in the accelerated senescence of WS cells. If this accelerated senescence is reflective of WS aging in vivo, these kinase inhibitors may well form the basis of antiaging therapies for individuals with WS.
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PMID:The role of cellular senescence in Werner syndrome: toward therapeutic intervention in human premature aging. 1746 Feb 11


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